Category: Preclinical Development
Purpose: Gamma-hydroxybutyric acid (GHB) is a Schedule I class drug that is highly abused by body builders, drug abusers, and used in drug-facilitated assaults. Reports related to GHB toxicity indicate that in 33-41% of the cases co-ingestion with alcohol occurred. Due to the ionization state of GHB at physiological pH, permeation through membranes is not possible, requiring facilitated transport. Our laboratory has previously reported that GHB is a substrate for the monocarboxylate transporters (MCT), which are important in its absorption, renal clearance and distribution across the blood-brain barrier (BBB). Our goal was to investigate the drug-drug interaction (DDI) between GHB-ethanol and a possible treatment for overdoses with GHB-ethanol.
Methods: The toxicokinetics (TK) of this DDI were investigated by examining plasma concentrations of GHB over time in the presence and absence of ethanol. The toxicodynamic (TD) parameters examined were respiratory depression (breathing frequency, tidal volume) and sedation. The novel MCT1 inhibitor AZD3965 was administered post-GHB administration to investigate its efficacy in reversing toxicity. Animals were placed on a plethysmography chamber in order to record respiratory parameters, and plasma and urine samples were collected. GHB was administered IV or orally at time zero, ethanol was administered (2 g/kg IV) 5 min before GHB administration and AZD 3965 as a dose of 5mg/kg IV 60 min after GHB administration. The sedation effect of this DDI was studied after oral administration of GHB. Sleep time is calculated by subtracting the time rats lose the righting reflex (LRR) from the time rats the righting reflex returns (RRR). One-way ANOVA followed by non-parametric test statistical analysis was performed utilizing GraphPad Prism 7. Parameters values are expressed as mean (SD), n= 3-7.
Results: Ethanol administration did not alter the pharmacokinetics (AUC, clearance) of GHB. Effect on respiration rate (breaths per minutes) was quantitatively determined by calculating the area below the effect curve (ABEC).
Toxicodynamic (TD) Parameters
GHB + Ethanol
GHB + Ethanol + AZD
Frequency ABEC (breaths)
Tidal Volume ABEC (mL/breath/min)
29.7 ( 4.7)*#
Sleep time (min)
Toxicokinetic (TK) Parameters
5.72 ( 0.99)
Marilyn Morris– SUNY Distinguished Professor and Chair, Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York